【Q&A】 加拿大衛生部發布PIC/S GMP附錄1—無菌藥品的生產(GUI-0119)問答
Q1：Does the supervisor of a sterile drug manufacturing facility need to have a degree in microbiology?
無菌藥品生產設施的主管是否需要具有微生物學學位？
A:Section C.02.029 (b) “Sterile drugs” of the Food and Drug Regulations requires that “a drug that is intended to be sterile shall be produced under the supervision of personnel trained in microbiology.” The expression “trained in microbiology” does not mean that this person must have a university degree in microbiology. However, the person must have taken university courses in microbiology.
答:《食品和藥品法規》第C.02.029（b）節“無菌藥品”規定“無菌藥品應在受過微生物學培訓的人員的監督下生產。”“受過微生物學培訓”並不意味著該人員必須擁有微生物學大學學位。但是，該人員必須修過微生物學的大學課程。
Q2：If water that has already been used in compounding is later found to contain endotoxins, what actions need to be taken?:
如果後來發現已經用於配料的水含有內毒素，需要採取什麼措施？
A：Water can be used for production before obtaining microbiological test results, but the results of these tests must be available before final release of the product. Good manufacturing practices permit release only after raw material and finished product testing is completed and results show the product complies with its specifications.
答：在得出微生物檢測結果之前，可將水用於生產，但在產品最終放行之前必須得出這些檢測的結果。只有在原料和成品完成檢測，並且結果表明產品符合其質量標準後，藥品生產質量管理規範才允許放行。
The appropriate action would include an investigation into:
適當的措施包括對以下方面進行的調查：
the potential sources of endotoxins
內毒素的潛在來源
the sanitation and maintenance of the water system
水系統的衛生和維護
Q3：Are sterile products in amber glass and plastic ampoules exempt from 100% inspection?:
琥珀色玻璃和塑膠安瓿瓶中的無菌產品是否可免于100%檢查？
A：No. You must inspect each final container of injections. The 100% inspection test does not limit itself to particulate matter. It also includes, for example, sealing defects, charring, glass defects, underfills and overfills, and missing print. Please refer to interpretation in the section on Finishing of sterile drugs. For parenteral products, there are more requirements for packaging (for example, the immediate container must be of a material and construction that allows visual or electronic inspection of the drug). Please refer to section C.01.069 “Limits of Variability” in the Food and Drug Regulations.
答：不是。必須檢查注射劑的每個最終容器。100%檢查測試並不僅限於顆粒物，還包括比如密封缺陷、炭化、玻璃缺陷、灌裝不足和過量以及印刷缺失。請參閱無菌藥品成品部分的解釋。對於注射劑產品，對包裝有更多要求（例如，內包裝容器的材料和結構必須便於對藥物進行目視或電子檢查）。請參閱《食品和藥品法規》第C.01.069節“可變限度”。
Q4：What are the room classification requirements for preparing containers and other packaging materials to be used in fabricating sterile drugs?
用於準備無菌藥品生產所需的容器和其他包裝材料的房間分級要求是什麼？
A：Normally, you would prepare (for example, clean, wash) containers and packaging materials in a “clean” room (Grades C or D). Afterwards, for drugs sterilized by filtration (and not further subjected to terminal sterilization in their final containers), you must depyrogenate and sterilize (using double-ended sterilizers or any other validated method) the containers and materials used before introducing them into aseptic rooms. The depyrogenation step can be done using pyrogen-free water for injection (WFI) for the last rinse before sterilization or by performing the depyrogenation and sterilization in one operation using a dry heat oven. Filling of these products normally takes place in a Grade A area with a Grade B background.
答：通常，在“潔淨”室（C級或D級）準備（例如，清潔、清洗）容器和包裝材料。之後，對於通過過濾除菌的藥物（不再在其最終容器中進行最終滅菌），在將其引入無菌室之前，必須對使用的容器和材料進行除熱原和滅菌（使用雙門滅菌櫃或任何其他經過確效的方法）。除熱原步驟可以使用無熱原注射用水（WFI）進行滅菌前的最後一次沖洗，也可以使用幹熱滅菌櫃一步完成除熱原和滅菌。這類產品通常在具有B級背景的A級區進行灌裝。
For products that are terminally sterilized, you do not have to use containers and packaging materials that are sterile. However, those in direct contact with the product should be free of pyrogen. This is usually done by using pyrogen-free WFI for the last rinse of these materials, unless they are later depyrogenated by another method (for example, using a dry heat oven).
對於最終滅菌的產品，不必使用無菌的容器和包裝材料。但是，與產品直接接觸的容器和包裝材料應無熱原。通常是使用無熱原WFI對這些材料進行最後一次沖洗，除非後續通過另一種方法（例如使用乾滅菌櫃）進行除熱原。
Also, the initial bioburden of these materials should meet pre-established limits, based on sound science. Keep the risk of contamination during their introduction in filling areas to a minimum.
而且，這些材料的初始生物負荷應符合基於可靠科學的預先設定限值。將其引入灌裝區域時的污染風險降至最低。
Q5：For the validation of moist heat sterilization cycles, will the new standards include the use of prions as the organism of choice (instead of Geobacillus stearothermophilus)?
對於濕熱滅菌程式的確效，新標準是否會使用普恩蛋白作為首選生物（而不是嗜熱脂肪土芽孢桿菌）？
A：At the present time, the scientific and pharmaceutical community recognizes the spores of Geobacillus stearothermophilus as the organisms of choice for validating moist heat sterilization cycles. The use of prions (infectious proteins) could be inadequate because their detection and quantification (which is based on animal models) is very difficult. Also, these proteins are very hard to destroy and could present a danger should they accidentally be spread in a plant.
答：目前，醫藥科學界認為嗜熱脂肪土芽孢桿菌孢子是確效濕熱滅菌程式的首選生物。使用普恩蛋白（傳染性蛋白質）可能是不夠的，因為其檢測和定量（基於動物模型）非常困難。此外，這些蛋白質很難被破壞，如果在廠房內意外傳播，可能會造成危險。
Q6：According to the monograph on parenteral products (0520) of the 10th edition of the European Pharmacopoeia (Ph. Eur.), injections for veterinary use with a volume dose of less than 15 mL are exempted from bacterial endotoxins/pyrogen testing by the European Union (EU). Is this interpretation correct? If so, would this EU exemption be applicable in Canada?
根據《歐洲藥典》第10版關於注射劑產品的各論（0520），歐盟（EU）豁免了體積劑量小於15毫升的獸用注射劑進行細菌內毒素/熱原檢測。這種解釋正確嗎？如果是這樣，這種歐盟豁免是否適用於加拿大？
A：Yes, this interpretation is correct. But this exemption does not apply in Canada.
答：是的，這種解釋正確。但這種豁免不適用於加拿大。
As per section C.01.067 (1) “Limits of Variability” in the regulations, each lot of a drug for parenteral use must be tested for the presence of pyrogens using an acceptable method. Each lot must be found to be non-pyrogenic. The bacterial endotoxins and pyrogen test methods described in the United States Pharmacopeia (USP) and Ph. Eur. are considered acceptable methods for that purpose.
根據法規第C.01.067（1）節“可變限度”，每批注射用藥物都必須使用可接受的方法進行熱原檢測。每批產品必須無熱原。美國藥典（USP）和歐洲藥典中描述的細菌內毒素和熱原檢測方法被認為是可接受的方法。
For all parenteral drug products, the bacterial endotoxins test should be preferred over the pyrogen test, unless the latter is shown to be justified (more appropriate) or has been approved by a review directorate. The specification of all drug products for parenteral use intended for the Canadian market should include a test for bacterial endotoxins or pyrogens. The current EU “15 mL exemption” does not apply in Canada.
對於所有注射用藥品，細菌內毒素檢測應優先于熱原檢測，除非後者被證明是合理的（更合適）或已獲得審查委員會的批准。針對加拿大市場的所有注射用藥品的質量標準應包括細菌內毒素或熱原檢測。目前歐盟的“15毫升豁免”不適用於加拿大。
The only acceptable exemptions are those provided in section C.01.067 (2) “Limits of Variability.” In other words, not testing a parenteral drug product for the presence of pyrogens would be considered acceptable only if documentation is available to show that the parenteral drug product is inherently pyrogenic or that it cannot be tested by any of the methods.
唯一可接受的是第C.01.067（2）節“可變限度”中規定的豁免。換句話說，只有在有檔證明注射用藥品本身具有致熱原性或無法通過任何方法進行檢測的情況下，才認為不檢測注射用藥品是否存在熱原是可接受的。
Q7：What is Health Canada’s position on pooling samples within the same batch (for example, 7 samples in 1 pool) for testing for sterility? The European Pharmacopoeia (Ph. Eur.) does not mention explicitly a pooling of samples for testing for sterility.
加拿大衛生部對將同一批樣品(例如，7個樣品合併在一起)合併用於無菌檢測的觀點是什麼？《歐洲藥典》（Ph. Eur.）沒有明確提及將樣品合併進行無菌檢測。
A：It is acceptable to pool samples for sterility testing with the membrane filtration method. But it is not acceptable to pool samples if you use the direct inoculation method. Exceptions can be tolerated when the volume of the sample pool does not exceed 10% of the culture medium volume.
答：可以使用膜過濾法將樣品合併進行無菌檢測。但如果使用直接接種法，則不能將樣品合併在一起。當合併後樣品總體積不超過培養基體積的10%時，則可以例外。
